Targeted alpha-radiation therapy for NTSR1-positive tumors using SKL35501/SKL35502

Inclusion Criteria

Participants are eligible to be included in the study only if all the following criteria apply:

1. Signed ICF.
2. Participants should be ≥ 18 years (in the US) or ≥19 years (in South Korea) of age at the time of signing the ICF.
3. Histologically and/or cytologically confirmed diagnosis of selected advanced or metastatic solid tumors (relapsed/refractory disease).
4. Selected advanced solid tumors (PDAC, CRC, BTC, HNSCC, EC, and GC) with sufficient target (NTSR1) expression confirmed by SKL35502 imaging as defined in Inclusion Criterion 5, that have progressed following at least one prior line of therapy or for which no other standard therapy with proven clinical benefit is currently available or recommended based on the Investigator's individual risk-benefit assessment. Patients with MSI-H/dMMR CRC must have previously received and progressed on, been intolerant to, or been deemed ineligible for an FDA-approved immune checkpoint inhibitor, unless such therapy is contraindicated.
5. Sufficient target (NTSR1) expression on SKL35502 imaging, defined as uptake above background in at least 1 RECIST v1.1 measurable lesion, with background activity defined in accordance with the Imaging Charter. For study eligibility, NTSR1 positivity will be determined locally at the site by the Investigator based on review by a qualified site nuclear medicine physician/radiologist, as applicable. SKL35502 images and required lesion documentation will also be submitted for central review for dosimetry, biodistribution, lesion alignment, image quality control, and consistency of image analyses across sites. Central review will not replace the site determination of eligibility except in equivocal cases requiring adjudication.
6. Patients with secondary metastasis to the CNS are eligible if they have had all brain metastases resected or have received radiation therapy ending at least 4 weeks prior to C1D1 and they meet all of the following criteria:

   1. Residual neurological symptoms ≤ Grade 1
   2. No glucocorticoids requirement or patients may be receiving low doses of glucocorticoids (not exceeding a dose equivalent to prednisone 10 mg daily), provided the dose has been stable for at least 2 weeks prior to C1D1
   3. Follow-up MRI or CT scan shows no progression of treated lesions and no new lesions.
7. Measurable disease on imaging, as assessed by RECIST v1.1 and/or RANO-BM for brain metastases (Eisenhauer et al, 2009).
8. ECOG performance status ≤ 2.
9. Minimum life expectancy ≥ 12 weeks at enrollment as determined by investigator
10. Willing to follow the contraception requirements as outlined:

    1. For females:

       WOCBP:
       * Must have a negative serum pregnancy test performed within (≤) 14 days prior to dosing with SKL35502 (where demanded by local regulations; test may be required within 24 hrs. prior to dosing).
       * Compliant with at least 2 highly effective contraceptive methods (e.g., oral contraceptives, IUD, condom with spermicide, etc.) throughout the study and for at least 8 months (i.e., corresponding to 5 half-lives + 6 months) following the last dose of SKL35501.
       * Female patients must not be pregnant or lactating at study screening and during the course of the study and must not become pregnant for at least 8 months (i.e., corresponding to 5 half-lives + 6 months) following the last dose of SKL35501.
       * Abstinence is not considered an adequate contraceptive method on its own.
       * Women of non-childbearing potential:
       * Must be surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy) or postmenopausal (defined as no menstrual cycle for at least 12 consecutive months).
    2. For males:

       * Must be surgically sterile, or compliant with a contraceptive method (effective barrier contraception, such as a condom with spermicide) during the study and then for at least 5 months (i.e., corresponding to 5 half-lives + 3 months) after the last dose of SKL35501.
       * Must agree not to donate sperm during the study until 90 days after the last dose of SKL35501.
       * Male patients with female partner(s) of childbearing potential:
       * Female partner must use a highly effective method of contraception (e.g., oral contraceptives, IUD, diaphragm, etc.) during the study and 5 months (i.e., corresponding to 5 half-lives + 3 months) following the male patient's last dose of SKL35501.
       * Male patients with female partner(s) of non-childbearing potential (i.e., postmenopausal or surgically sterile for at least 6 months prior to Screening):
       * No additional contraception method is required.
11. Adequate hematologic and end-organ function, defined based on the following laboratory results obtained within (≤) 14 days prior to C1D1:

    1. ANC ≥ 1.5 × 109/L (1500/μL), without G-CSF support. G-CSF may be administered until (\>) 14 days prior to C1D1.
    2. Platelet counts ≥ 100 × 109/L (100,000/μL) without receiving any thrombopoietin receptor agonists, other therapies for thrombocytopenia or platelet transfusion for ≥ 14 days prior to C1D1.
    3. Hemoglobin ≥ 90 g/L (9 g/dL). Patients may be transfused or receive erythropoietic treatment to meet this criterion until (\>) 14 days prior to C1D1.
    4. AST and ALT ≤ 3 × ULN (≤ 5 × ULN for patients with documented liver metastases).
    5. Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients with Gilbert's syndrome).
    6. eGFR ≥ 60 mL/min (multiply the estimate of GFR by individual's BSA (calculated using an appropriate formula) and divide by 1.73 m2).
    7. Albumin \> 28 g/L

Exclusion Criteria

Patients are excluded from the study if any of the following criteria apply:

Medical Conditions:

1. Patients with evidence of hydronephrosis.
2. History of solid tumor malignancy other than the diseases under study, diagnosed within (≤) the last 3 years of study enrollment, excluding adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer, in situ breast cancer, in situ prostate cancer (patients must have shown no evidence of active disease for 2 years prior to enrollment).
3. History of ascites or pleural effusion, unless successfully treated, asymptomatic, and not requiring treatment for \> 2 months prior to C1D1.
4. History of and/or current cardiovascular events or conditions:

   1. History of myocardial infarction, unstable or severe angina, or arterial thrombotic event (such as CVA or TIA) within (≤) 12 months prior to C1D1
   2. Current NYHA stage II-IV congestive heart failure
   3. Unstable arrhythmia, or history or presence of a clinically significant (in the Investigator's opinion) ECG abnormality
   4. Screening QT (QTc) interval (average of triplicate measurements; corrected for heart rate using Fridericia's formula) \> 470 msec
   5. Uncontrolled hypertension, defined as SBP \> 150 mm Hg and/or DBP \> 100 mm Hg at screening, despite optimal antihypertensive therapy.
5. Positive tests at screening for the following:

   1. HIV: HIV patients on established ART for at least 4 weeks and have a viral load less than 400 copies/mL and CD4+ T-cell counts ≥350 μL may be eligible.
   2. HBsAg: Patients with positive HBV test and HBV DNA \< 500 copies being treated with antivirals may participate.

   i. HBcAb: Patients with a positive HBcAb test followed by a negative HBV DNA test at screening may be enrolled.

   ii. HCV antibody test: Patients with a positive HCV antibody test followed by a negative HCV RNA test at screening may be enrolled.
6. Active thrombophlebitis, thromboembolism, hypercoagulability states, bleeding:

   1. Patients with a history of DVT may participate if successfully treated, completely resolved, and no treatment has been given for \> 2 months.
   2. Patients who suffered a thromboembolism \> 6 months prior and who are stable on anticoagulation may participate.
7. Uncontrolled diabetes.
8. Chronic severe liver disease or liver cirrhosis.
9. Any active or symptomatic persistent infection (bacterial, viral, or fungal) requiring systemic therapy within (≤) 14 days prior to C1D1.
10. Any psychiatric illness or social situation that would limit compliance with study requirements.
11. Any other significant co-morbidity, disease, metabolic dysfunction, physical examination, or clinical laboratory finding that contraindicates the use of an investigational drug, or may represent an unacceptable risk from treatment complications, or may affect adherence to the study procedures or the interpretation of the results.

    Ineligible prior and ongoing treatment requirements:
12. Treatment with previous cancer therapies (including investigational cancer treatment) ≤ 28 days or 5 half-lives prior to C1D1, or radiation therapy within (≤) 4 weeks prior to start of SKL35502 (palliative radiation or stereotactic radiosurgery within (≤) 7 days prior to start of SKL35502). Patients must have recovered from all acute radiotherapy-related toxicities.
13. Prior radiopharmaceutical or radioligand therapy.
14. Patients who are receiving treatment with medications known to prolong the QT/QTc interval.
15. Live, attenuated vaccine within (≤) 28 days prior to C1D1, or anticipation of need for such a vaccine during the course of the study. COVID-19 vaccination is acceptable.
16. Any other therapy that is prohibited during the study. Refer to Section 6.9.1.

    Other Exclusion Criteria:
17. Known hypersensitivity to SKL35502 or SKL35501 or any component(s) of SKL35502 or SKL35501.
18. Contraindications to or inability to perform the imaging procedures required in this study.
19. History of drug-induced anaphylactic or other severe hypersensitivity reactions.
20. History of any of the following: drug-induced SCAR; including but not limited to SJS/TEN, or DRESS syndrome), or dose-limiting immune-mediated reactions.
21. Current pregnancy and/or breast-feeding.